Therapeutics based on α radiation provide a promising alternative to conventional methodologies (e.g., γ radiation and β− radiation) because α radiation relatively short particle range results in substantially lesser radiation to neighboring tissue. Specifically, instead of being used to treat large, solid tumors, α particles have a greater potential for application to small, disseminated tumors, and micro metastases. Development of effective α therapeutics would also provide a boon to treatment of hematological malignancies consisting of individual, circulating neoplasmic cells. Compared with β− radiation, α radiation provides a very high relative biological effectiveness, killing more cells with a lower activity. This effect results from the high linear energy transfer of α particles, inducing more DNA double strand breaks per decay than their β− counterparts. Additionally, due to the direct action of α radiation on DNA without free radical intermediaries, it remains unaffected by hypoxic environments and cell cycle considerations. Further, a relatively low γ component in the decay of alpha emitters tends to allow for outpatient treatments while also making it easier to protect nuclear medicine personnel.
Nevertheless, α emitters pose distinct chemical problems for their development and therapeutic use. Several radionuclide options emit multiple α particles in their decay chain. These therapeutic in vivo generator systems can deliver a relatively large amount of energy in a localized space (e.g., 225Ac and daughters deliver >27 MeV of energy). Unfortunately, if long-lived daughter products are not retained within the structure of the therapeutic, they are likely to migrate to non-target tissue. Generally, the first α emission provides enough recoil energy on the parent nucleus to sever any metal-ligand bond thereby releasing the daughter radionuclide from the targeting agent. Nanoparticles represent a desirable solution for an in vivo α radiation generator in that they represent a good size balance—small enough to have a targeting ability similar to that of small molecules but large enough to contain at least some radioactive decay daughters. In addition to sequestering at least some of the radioactive decay daughters due to their size, nanoparticles are believed to reduce kidney toxicity because they tend to be cleared preferentially through the liver, spleen, and other areas of the reticuloendothelial system rather than the renal system.
Of particular interest for therapeutic in vivo α radiation generator nanoparticles are LaPO4 nanoparticles doped with 225Ac (see, e.g., Imaging of vascular targeted LaPO4 nanoparticles doped with actinium-225, Kennel et al., Poster Session 2d: Development/Novel Use of Imaging Probes, Sep. 25, 2009) but such nanoparticles have several shortcomings. For example, such 225Ac-doped LaPO4 nanoparticles tend to only sequester about 50% of the radioactive decay daughters (e.g., 221Fr). Additionally, the surfaces of such 225Ac-doped LaPO4 nanoparticles are not readily functionalized such that the nanoparticles are generally considered to substantially target particular tissue types or locations in a body being treated therewith. Thus, a need still exists for nanoparticles doped with α emitting radionuclides having one or more of the following properties: improved retention or sequestration of radioactive decay products and surfaces that are readily functionalized so that the nanoparticles upon administration to a patient tend to target a desired tissue type(s) or location(s) in the body.